Retrieved from DalSpace, the institutional repository of ...

Retrieved from DalSpace, the institutional repository of

Dalhousie University http://dalspace.library.dal.ca/handle/10222/74955 Version: Post-print Publisher’s version: Baker, A. E., Marchal, E., Lund, K. L. A., & Thompson, A.

(2014). The use of tin (IV) chloride to selectively cleave benzyl esters over benzyl ethers

and benzyl amines. Canadian Journal of Chemistry, 92(12), 1175-1185.

https://doi.org/10.1139/cjc-2014-0364

1

The Use of Tin (IV) Chloride to Selectively Cleave Benzyl Esters over 1

Benzyl Ethers and Benzyl Amines 2

Alexander E. G. Baker, Estelle Marchal, Kate-lyn A.R. Lund and Alison Thompson* 3

Department of Chemistry, Dalhousie University, PO BOX 15000, Halifax, NS, B3H 4R2, Canada 4

*[email protected] 5

ABSTRACT: Benzyl esters are cleaved upon reaction with SnCl4, resulting in isolation of the corre-6

sponding carboxylic acid. Importantly, benzyl ethers, amines and amides do not undergo debenzylation 7

under these conditions, nor do a variety of other common protecting groups for alcohols, thereby render-8

ing SnCl4 selective amongst Lewis acids. The scope, tolerance and limitations of the strategy are 9

demonstrated through the analysis of several multi-functional substrates, including those bearing Cbz 10

groups. 11

Keywords 12

Benzyl ester, deprotection, protecting group, chemoselective debenzylation. 13

Introduction 14

The use of protecting groups is essential to much of modern organic chemistry, despite admirable exam-15

ples of natural product syntheses that lean to the contrary.1 The benzyl protecting group is of particular 16

interest courtesy of the fact that it may be easily removed using hydrogenolysis, by virtue of properties 17

inherent to the benzylic position.2,3 Although there is a plethora of reported conditions under which de-18

benzylation may be achieved,2,3 palladium-catalyzed hydrogenolysis is the most commonly adopted 19

tactic. As such, benzyl-protected ethers, amines and acids may be deprotected in a manner that is or-20

2

thogonal to methods employed for alkyl-protected functional groups. However, hydrogenolysis falls 1

short of being the ideal deprotection strategy. For most substrates and routine sets of conditions, the re-2

action set-up for hydrogenolysis may also effect the hydrogenation of unsaturated bonds. Furthermore, 3

benzyl ethers, amines and esters are often hydrogenolyzed concurrently. Additionally, safety considera-4

tions are essential when manipulating hydrogen gas and hydrogenolysis apparatus. We herein report the 5

scope and limitations of using SnCl4 to selectively debenzylate esters and carbamates. Benzyl (and some 6

other) ethers, benzyl amines, benzyl amides, alkyl esters, double bonds and triple bonds are inert to the-7

se reaction conditions. Although it is widely understood that Lewis acids often effect O-R cleavage, the 8

selectivity of SnCl4 to induce benzyl ester and carbamate cleavage over benzyl ethers and amines has 9

not yet been realised. 10

Results and discussion 11

Benzyl esters are often used in pyrrole syntheses to protect, and easily deprotect, the 2-position of pyr-12

roles.4 Deprotection is routinely achieved via hydrogenolysis, enabling facile and orthogonal pyrrole 2-13

carboxylate deprotection over alkyl ester substituents. We were thus intrigued when a Friedel-Crafts 14

acylation of 2 resulted not only in the anticipated product 3 but also the debenzylated analog 4 after 15

acidic work-up (Scheme 1, note that the ethyl ester moiety within 4 was intact). 16

17

Scheme 1. Benzyl ester cleavage accompanied SnCl4-promoted Friedel-Crafts acylation 18

A careful review of literature pertaining to the cleavage of esters and ethers using Lewis acids 19

(Table 1) revealed that each reagent promotes its own characteristic reactivity. For example, AlCl3 in 20

combination with anisole or N,N-dimethylaniline is the most commonly used Lewis acid for the cleav-21

3

age of benzyl esters,5-7 yet this system exhibits poor selectivity as it also cleaves tert-Bu5 esters as well 1

as benzyl and PMB ethers8,9 (entry 1). Alkyl esters can be hydrolyzed using a combination of AlCl3 and 2

N,N-dimethylaniline, thereby only the use of AlCl3-anisole6 allows for the selective deprotection of ben-3

zyl esters and ethers in the presence of alkyl esters. BCl3 has been used for benzyl ether debenzylation,10 4

and has some application for benzyl11-14 and alkyl ester11 cleavage (Entry 2). Indeed, the hydrolysis of 5

alkyl esters requires higher loading of BCl3 and/or longer reaction times,11,15 and thus selective benzyl 6

ether cleavage is possible in the presence of alkyl esters.10 It is also possible to selectively deprotect a 7

benzyl ester in the presence of an alkyl ester using BCl3,16,17 but no selectivity seems possible between a 8

benzyl ester and a benzyl ether.18,19 TiCl4,5,20-22 FeCl3,23-25 (Re(CO)4Br)223 and Sc(CTf3)3

26 are used to a 9

lesser extent to remove the benzyl moiety from esters, and their selectivity towards other functionalities 10

is not evident from the literature (Entries 3-6): however, they all cleave benzyl ethers. CeCl3 is highly 11

selective for the hydrolysis of tert-Bu esters and PMB ethers, leaving benzyl esters and benzyl ethers 12

untouched (Entry 7).27-29 It is nevertheless possible to reduce an alkyl or benzyl ester to its correspond-13

ing alcohol using a combination of CeCl3 and NaBH4. 30,31 The use of ZrCl4 was also studied for its abil-14

ity to cleave PMB esters and PMB ethers selectively over other ethers (Entry 8).32 15

SnCl4 has been shown to induce the de-O-benzylation33 of particular polybenzyl ethers in mono-16

saccharides, whereby precise stereochemical orientation of multiple ethereal groups is essential to pre-17

complexing the Lewis acid to achieve the desired reactivity (Entry 9). The use of SnCl4 was also report-18

ed for the hydrolysis of cephalosporin tert-Bu esters.20 Furthermore, a dimeric tin adduct has been used 19

to cleave acetates of substituted uridines,34 and TBTO [bis(tri-n-butyltin)oxide] has been used to cleave 20

alkyl and benzyl esters of amino acids.35 However, to the best of our knowledge, SnCl4 has not been 21

reported as a reagent by which to achieve the debenzylation of benzyl esters. Furthermore, Table 1 re-22

veals that Lewis acids have not previously been reported to effect selective debenzylation of esters over 23

ethers. 24

25

4

Table 1. Literature review of alkyl and benzyl ester and ether cleavage using Lewis acids; “✓” indi-1

cates complete conversion to the corresponding acid or alcohol; n.r. = no reaction. 2

Entry Lewis acid RCO2Bn RCO2PMB RCO2tBu RCO2Me ROBn ROPMB

1 AlCl3 a✓

5,6 b✓

7 b✓

5 c✓

6 a✓

8,9 c✓

9

2 BCl3 ✓12,16,17 ✓

14 ✓11,15 ✓

10 ✓13

3 TiCl4 ✓5 ✓

20 ✓21 ✓

22

4 FeCl3 ✓23 ✓

24 ✓23,25

5 (Re(CO)4Br)2 ✓23 incomplete23

6 Sc(CTf3)3 ✓26 ✓

26 ✓26

7 CeCl3 n.r.27 ✓28 n.r.28 n.r.29 ✓

29

8 ZrCl4 ✓32 n.r.32 ✓

32

9 SnCl4 ✓20 d

✓33

ain combination with anisole or N,N-dimethylaniline; bin combination with anisole; cin combination with N,N-dimethylaniline; donly 3

with elaborate polyol substrate. 4

To investigate the utility of SnCl4 as a reagent for the debenzylation of esters, benzyl benzoate 5

was used as a model substrate. At room temperature and using 1.2 equiv SnCl4, benzoic acid was thus 6

isolated in 79 % yield (Table 2, Entry 1). We then discovered that just 0.5 equiv SnCl4 was sufficient 7

for the debenzylation to be achieved in good yield. Furthermore, the reaction was tolerant to the pres-8

ence of trace amounts of water. The use of DCE as solvent gave comparable results, yet the reaction 9

yielded only starting material when THF and CH3CN were employed, presumably due to Lewis ac-10

id/base adduct formation. With 0.5 equiv SnCl4 in CH2Cl2 the reaction proceeded efficiently at reflux 11

temperature (Table 2, Entry 2), and so these became our conditions of choice, although complete con-12

version was also observed using either hexane or toluene at 40°C. To verify that the observed benzyl 13

5

deprotection was not caused by hydrolysis of SnCl4 and thus liberation of HCl, benzyl benzoate was 1

reacted with 2.4 equiv of an anhydrous hydrochloric acid solution in ether with 1 equiv water. After 24 2

h, no reaction was observed and the benzyl ester was isolated with 98% recovery. We also ascertained 3

that SnO2 (the byproduct of the quench of SnCl4 with water) was not the reaction catalyst: reacting 0.5 4

equiv of SnO2 with benzyl benzoate in CH2Cl2 for 16 h did not result in cleavage of the benzyl ester. 5

Table 2. SnCl4-induced ester debenzylation 6

7

entry equiv

SnCl4

temperature

(ºC)

time

(h)

isolated yield

of 6a (%)

1 1.2 25 19 79

2 0.5 40 6 80

8

To further explore the scope of SnCl4-induced ester debenzylation, compounds incorporating ad-9

ditional functionality were explored. Aryl esters bearing electron-withdrawing and electron-donating 10

groups underwent smooth cleavage to give excellent yields of the corresponding benzoic acids (Table 3, 11

Entries 2-3). Benzyl alkanoates were debenzylated in an equally successful manner (entries 4-6), as was 12

a benzyl phenyl acetate (Entry 7). Remote and conjugated double bonds were stable to the SnCl4-13

induced debenzylation reaction conditions, and enabled isolation of unsaturated carboxylic acids as well 14

as cinnamic acid (Entries 8 and 9). Triple bonds also proved stable (Entry 10). p-Methoxybenzyl esters 15

underwent smooth deprotection (Entries 11-13). 16

17

Table 3. Scope of SnCl4-induced debenzylation of esters 18

6

1

entry 5 6 (yield, %)a entry 5 6 (yield, %)a

1 5a

6a (80) 8 5h

6h (quant)

2 5b

6b (quant) 9 5i 6i (90)

3 5c

6c (92) 10 5j 6j (quant)c

4 5d

6d (82) 11 5k 6d (85)

5 5e

6e (80)b 12 5l 6f (80)

6 5f

6f (quant) 13 5m 6a (86)

7 5g

6g (96)

aisolated yields of 6 after complete reaction of 5 according to analysis using TLC; b1.2 equiv SnCl4; cperformed in NMR 2

tube, quantitative 3

7

1

To further study the scope of cleaving benzyl esters using SnCl4, several b-carbonyl-a-benzyl 2

ester pyrroles were subjected to the reaction conditions. However, only moderate yields of the corre-3

sponding acids could be obtained, and analysis using TLC suggested that decomposition of the products 4

occurred under the reaction conditions, making the purification challenging. A recent study reported the 5

ability of SnCl4�5H2O to promote the ring-opening of 4,5-dihydropyrroles,36 supporting the notion that 6

this Lewis acid can invoke a multitude of mechanisms involving the carbonyl moiety. 7

Nevertheless, with efficient conditions in hand we investigated whether the cleavage strategy 8

was general for esters or selective to the benzyl moiety and subjected several substrates to our optimised 9

reaction conditions (Table 4, SnCl4 0.5 equiv, DCM, 40 °C, 6h). In agreement with the literature, a tert-10

Bu ester was cleaved in the presence of SnCl4, but with only 0.5 equiv (Lit:20 4 equiv SnCl4 used, Entry 11

Ph OBn

O OBn

O

O2N

OBn

O

MeO

OBn

O

OBn

O

12tBu OBn

O

OBn

OMeO

5a 5b 5c

5d 5e 5f

5g

OBn

O

5h 5i

OBn

O

OBn

O

5j

OPMB

O

5k

tBu OPMB

O

5l

Ph OPMB

O

5m

8

1). Gratifyingly, only starting material was returned when ethyl benzoate 7b (Entry 2) was treated with 1

SnCl4, even when the stoichiometry was increased to 1.2 equiv SnCl4. Thus a benzyl ester could be easi-2

ly removed in the presence of an ethyl ester (Entry 3). Benzyl amines and amides are inert to the depro-3

tection reaction conditions (Entry 4-5). In contrast, the benzyl carbamate 7f was successfully cleaved, 4

albeit using 1.5 equiv SnCl4, to presumably allow for non-productive complexation to the nitrogen het-5

eroatom (Entry 6). Importantly, no reaction occurred using the same conditions with the Troc-like ben-6

zyl carbamate 7g and the starting material was completely recovered after 20 h (Entry 7). 7

Table 4. Scope of the reactivity of SnCl4 with various protecting groups 8

9

entry substrates recovered compounds

(yield, %)a

1 7a 6a (76)

2 7b SMb (96)

3 7c 8c (79)

4 7d SMb (99)

5 7e SMb (quant)

6 7f 8f (79)c

7 7g SM

(quant)c

aisolated yield; bSM = smarting material; c1.5 equiv of SnCl4, 20 h. 10

9

1

We then assessed the stability/reactivity of other alcohol protecting groups in the presence of 2

SnCl4 (Table 5). Primary benzyl alkyl ethers were inert to the reaction conditions (Entry 1). Although 3

the secondary benzyl alkyl ether 7h was recovered in 95% yield, traces of the alcohol were observed 4

using TLC (Entry 2). Phenol benzyl ethers substituted with an electron withdrawing group remained 5

untouched in the presence of SnCl4 (Entry 3), yet phenol benzyl ethers substituted with electron donat-6

ing groups were quantitatively cleaved (Entry 4-5), indicating that the use of benzyl groups to protect 7

(poly)phenols can be engineered so that selective deprotection may be achieved via the use of SnCl4. 8

The tosyl protecting group was inert under the reaction conditions (Entry 6). THP was readily removed 9

in just a few minutes (Entry 7). Removal of the MOM group under the reaction conditions was ob-10

served, as were several side products (Entry 8). The TBDMS protecting group was partially cleaved in 11

Ph

O

OtBu

Ph OEt

O

4

NBn

NH

O

NH

OBn

O

Ph

O

OH

NH2

NH

O

O Ph

CCl3

7a

EtO

O O

OBn 4EtO

O O

OH

6a

7b

7c 8c

7d

7e

7f

7g

8f

10

the presence of SnCl4, but more robust TIPS-protected alcohol was recovered (85%) after 6 h of reac-1

tion and only traces of the alcohol were observed using TLC (Entry 9-10). 2

Table 5. Scope of the reactivity of SnCl4 with alcohol protecting groups 3

4

entry substrates compounds (yield, %)a

1 7h SMb recovered (quant)

2 7i SMb recovered (97)c

3 7j SMb recovered (95)

4 7k 8kd

5 7l 8ld

6 7m SMb recovered (quant)

7 7n 8n (84)e

8 7o -f

9 7p SMb recovered (85)c

10 7q SMb recovered (36)

aisolated yield; bSM = starting material; ctraces of deprotected material could be observed using TLC; dnot isolated, com-5

plete conversion according to analysis using TLC; e5 minutes of reaction; fpartial conversion and formation of side-6

products 7

11

1

The orthogonal deprotection of benzyl-protected carboxylic acids within difunctional substrates 2

was then attempted, first in the presence of a benzyl ether (7r, Table 6, Entry 1) and also in the presence 3

of a benzyl amine (7s,37,38 Entry 2). However, although complete consumption of the starting materials 4

was observed in both cases, intractable mixtures resulted, with the 1H NMR spectra of the crude reaction 5

mixtures suggesting only decomposition. Fuelled by recent work regarding the relevance of evaluating 6

the scope and tolerance of new methodology by using multi-functional substrates vs. using multiple 7

additives each bearing different functional groups,39 we were intrigued by our results, given that the 8

benzyl ethers 7h and 7i (Table 5), and the benzyl amine 7d (Table 4), had been stable in the presence of 9

OBn

OBn

OBnEtO2C

OBn

OBnMeO

OTs

OTHP

OMOM

OTIPS

OTBDMS

OH

OHMeO

OH

7h

7i

7j

7k

7l

7m

7n

8k

8l

8n

7o

7p

7q

12

SnCl4. We thus performed an experiment involving benzyl benzoate and SnCl4, dissolved in CD2Cl2 1

alongside one equivalent of diethyl ether as an additive. The reaction did not reach completion after the 2

expected 5 h at 40 °C, despite the fact that benzyl benzoate underwent complete cleavage in the absence 3

of diethyl ether (Table 3, Entry 1). Instead, 1H NMR analysis of the reaction mixture after 24 h indicated 4

a benzyl benzoate/benzoic acid ratio of 1:7.3, alongside complexation of the diethyl ether to SnCl4 as 5

suggested by the chemical shift of the CH2 protons (cf. Supporting Information). Clearly the complexa-6

tion of the ether to the SnCl4 reagent slowed down the desired ester debenzylation process. This was 7

confirmed when using the dibenzyl-containing serines 7t and 7u (Table 6, Entries 3 and 4, respectively), 8

both of which required 1 equivalent of SnCl4 to produce the expected substrates via chemoselective 9

debenzylation, albeit in moderate yield. Although mono benzyl ethers are stable under our reaction con-10

ditions (Table 5), a poly benzyl ether (7u) was partially deprotected, and 57% of starting material was 11

recovered (Table 6, Entry 5) presumably because of the close proximity of functional groups capable of 12

complexation to the Lewis acid.33 Those experiments demonstrate the limitations of the use of SnCl4 as 13

a debenzylating agent for some substrates. Indeed, the strong Lewis acid properties of this reagent, as 14

well as its complexation properties, should always be anticipated when considering the use of SnCl4 to 15

effect debenzylation. 16

17

18

19

20

21

22

23

24

25

13

Table 6: Scope of the reactivity of SnCl4 with substrates bearing multi-functionality. 1

2

entry substrates compounds (yield, %)a

1 7r Decomp.

2 7s Decomp.b

3 7t 8t (55)b

4 7u 8u (30)b

SMc (24)

5 7vd SMc recovered (57)e

aisolated yield; b1 equiv of SnCl4, overnight; cSM = starting material; dα/β 1:6.2; e α/β 3.2:1 3

4

BnO2C

OBn

CO2Bn

OBnHN

BnONHCbz

O

OMe

BnO

NHBn

O

OBn

OBnOBnO

OBn

OBn

BnONH2

O

OMeHCl

OBn

BnONHBn

O

OH

7r

7s

7t

7u

7v

8t

8u

14

Turning to the potential mechanism for SnCl4-induced ester debenzylation, we used NMR stud-1

ies (Figure 1) to follow the course of benzyl benzoate deprotection. As expected, 1H spectra recorded 2

over time revealed the decrease of the CH2 signal of the benzyl ester (originally at 5.4 ppm), alongside 3

the gradual appearance of aryl signals corresponding to benzoic acid. Curiously, the characteristic ben-4

zylic signal of benzyl chloride appeared at 4.6 ppm, yet the signal intensity decreased with extension of 5

the reaction time (compare Figure 1c recorded after 1 hour to Figure 1e recorded after 6 h). The for-6

mation of benzyl chloride was previously observed upon the deprotection of poly benzyl ethers using 7

SnCl4,33 and this Lewis acid has been reported to induce calixarene formation from 4-tertbutyl phenol,40 8

lending support to the belief that the liberated benzyl moiety undergoes further reaction to form a poly-9

meric species. 10

11

Figure 1. 1H NMR (300 MHz) of benzyl benzoate deprotection at 30 °C; (a) benzyl benzoate in CD2Cl2; 12

(b) addition of SnCl4 (0.5 equiv); (c) reaction after 1 h; (d) reaction after 3 h; (e) reaction after 6 h; (f) 13

benzoic acid and SnCl4 (0.5 equiv) in CD2Cl2; (g) benzoic acid in CD2Cl2. Note that the broad areas 14

across (d) and (e) at d 3.8 and 7.1 ppm are indicative of the by-product (9). 15

We also noted that the reactions produced a by-product (9). Upon isolation as a crystalline white 16

solid, compound 9 exhibited 1H NMR characteristics (see Supporting Information) that matched the 17

15

broad aryl and benzylic signals that appeared as the ester debenzylation proceeded (see Figure 1d and 1

1e). Analysis using APCI+ mass spectrometry revealed that 9 was polymeric, with a repeating benzylic 2

unit (mass 90 m/z, see Supporting Information). Furthermore, the reaction of benzyl chloride with 0.5 3

equiv of SnCl4 in CH2Cl2 for 21 hours, gave a crystalline white solid. The corresponding 1H NMR spec-4

trum exhibited the same two broad signals as the material isolated after the ester debenzylation reaction 5

(7.1 and 3.8 ppm), with similar polymeric mass spectral data (see Supporting Information). A related 6

polybenzyl species was observed after benzyl ester cleavage using a rhenium catalyst, and can be pre-7

vented using mesitylene as a scavenger of the benzylic cation.23 Anisole has been shown to play the 8

same role when using AlCl3 for removal of the benzyl moiety from benzyl esters.5 9

The coordination of SnCl4 to ethyl esters has previously been demonstrated using IR spectrosco-10

py.41 Based on the postulated mechanism for SnCl4-induced debenzylation of polybenzyl ethers,33 we 11

propose an ester debenzylation mechanism whereby pre-coordination of tin to the oxygen atoms of the 12

benzyl ester facilitates delivery of chloride to the electrophilic benzylic position. Such delivery would 13

not occur in the case of alkyl esters, since the corresponding O–CH2R functionality would be insuffi-14

ciently activated. In this respect, the distinguishing electronic properties of the benzylic position render 15

benzyl esters, and not benzyl ethers, uniquely susceptible to SnCl4. However, the presence of other moi-16

eties capable of coordinating to SnCl4 would evidently disrupt the desired coordination to the ester func-17

tionality thus slowing the debenzylation and/or altering the course of the reaction and so, as for most 18

deprotection strategies, each substrate should be considered for its functionality and its likelihood to 19

interact with SnCl4 in the desired manner. We analysed NMR data for signs of coordination of SnCl4 to 20

benzyl carboxylates. The 119Sn NMR spectrum of a sample of benzyl benzoate and 2.5 equiv SnCl4 re-21

veals an upfield shift (Figure 2b) c.f. SnCl4 alone (Figure 2a), and significant signal broadening. Such 22

broadening and coordination is less dramatic for SnCl4 and benzoic acid (Figure 2c), indicating much 23

greater Sn interaction with benzyl esters than carboxylic acids. 24

16

1

Figure 2. 119Sn NMR (112 MHz), -80 °C; (a) SnCl4 in CD2Cl2, d -155.4 ppm; (b) ten mins after addition 2

of benzyl benzoate, d -204.1 ppm; (c) benzoic acid and SnCl4 in CD2Cl2 after ten mins, d -155.7 ppm. 3

4

5

6

7

Conclusion 8

In summary, SnCl4 cleaves benzyl esters and carbamates yet leaves benzyl amides, double bonds and 9

triple bonds intact. Benzyl alkanoates and aryl esters were successfully cleaved in high yields. While 10

simple benzyl ethers remain unreacted, the suitability of SnCl4 should be considered carefully when the 11

substrate presents multiple benzyl ethers as tin complexation to multiple oxygen atoms can induce ben-12

zyl ether cleavage. The orthogonality of cleaving benzyl esters and carbamates, cf. benzyl ethers, is sub-13

strate dependant, presumably due to the intrinsic strong Lewis acid properties of SnCl4. NMR analysis 14

suggests that a crucial coordination of SnCl4 with the oxygen atoms of the ester facilitates chloride at-15

tack at the benzylic position to cleave the O–CH2Ph bond. Alongside the requisite carboxylic acid, the 16

reaction produces a polybenzylic material. Although the method suffers some limitations we believe that 17

benzyl deprotection using SnCl4 offers an alternative route for the debenzylation of esters for organic 18

and total synthesis. The potential to use SnCl4 for the chemoselective cleavage of benzyl esters and car-19

bamates, over benzyl ethers, amides and amines complements strategies that use catalytic transfer hy-20

drogenation,42 NBS,43 silica-supported NaHSO4,44 NiCl2/NaBH445 and Raney Ni.46 21

EXPERIMENTAL SECTION 22

17

General Experimental Procedures: All reactions were carried out under a nitrogen atmosphere using 1

septa-sealed solvents under anhydrous conditions. All reagents and solvents, including anhydrous 2

CH2Cl2, were used as received unless otherwise stated. SnCl4 (99%) was anhydrous and fuming, hex-3

anes and dichloromethane used for chromatography were obtained crude and were purified via distilla-4

tion under air and at 1 atm. before use. Column chromatography was performed using 230-400 mesh 5

ultra pure silica gel. Mass spectra were obtained using TOF and LCQ Duo ion trap instruments operat-6

ing in ESI+ or APCI+ mode. 1H NMR, 13C NMR and 119Sn spectroscopy were used for chemical charac-7

terization and purity analysis using 300 and 500 MHz spectrometers. All chemical shifts are expressed 8

in parts per million (ppm). The CDCl3 singlet was calibrated to 7.26 ppm for 1H NMR and 77.36 ppm 9

for 13C NMR; the CDCl2 signal was set to 5.31 ppm for 1H NMR and 53.80 ppm for 13C NMR; the 10

DMSO signal was set to 2.50 ppm for 1H NMR; the CD3OD signal was set to 3.31 ppm for 1H NMR; 11

119Sn spectra were referenced against SnMe4 set to 0 ppm as an internal reference. Coupling constants 12

(J) are reported in Hertz (Hz). Splitting patterns are indicated as; broad (br), singlet (s), doublet (d), tri-13

plet (t), apparent triplet (at), quartet (q), apparent quartet (aq), quintet (qn), sextet (se), multiplet (m). 14

The following compounds were prepared via established procedures: monoethyl glutarate (1),47 15

benzyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (2),48 benzyl benzoate (5a),49 benzyl 4-nitrobenzoate 16

(5b),50 benzyl 4-methoxybenzoate (5c),51 benzyl pentanoate (5d),52 benzyl tetradecanoate (5e),53 benzyl 17

pivalate (5f),54 benzyl 2-(4-methoxyphenyl)acetate (5g),55 benzyl pent-4-enoate (5h),56 4-18

methoxybenzyl pivalate (5l)57 and 4-methoxybenzyl benzoate (5m), 50 tert-butyl benzoate (7a),58 ethyl 19

benzoate (7b),59 N-benzyl-N-methyl-2-phenylethanamine (7d),60 N-benzyl-3-methylbutanamide (7e),61 20

benzyl (3-phenylpropyl)carbamate (7f),62 (3-(benzyloxy)propyl)benzene (7h),63 ethyl 4-21

(benzyloxy)benzoate (7j),64 1-(benzyloxy)-4-methylbenzene (7k),65 1-(benzyloxy)-4-methoxybenzene 22

(7l),66 3-phenylpropyl 4-methylbenzenesulfonate (7m),67 2-(3-phenylpropoxy)tetrahydro-2H-pyran 23

(7n)68 (NMR data were in agreement with the literature),69 triisopropyl(3-phenylpropoxy)silane (7p) and 24

18

tert-butyldimethyl(3-phenylpropoxy)silane (7q),70 benzyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside 1

(7v).71 2

Preparation of starting material 3, 4, 5 and 7: 3

Benzyl 4-(5-ethoxy-5-oxopentanoyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate (3) and 4-(5-ethoxy-5-4

oxopentanoyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (4): To monoethyl glutarate 147 (3.75 g, 23.4 5

mmol), thionyl chloride (2.1 mL, 29.3 mmol) was added. The reaction was heated to 60°C for 30 6

minutes and then 80 °C for 1 h. Thionyl chloride was removed in vacuo to afford the acid chloride as a 7

yellow oil which was used without further purification (4.2 g, quantitative). 8

Benzyl 3,5-dimethyl-1H-pyrrole-2-carboxylate 2 (4.8 g, 21 mmol) was dissolved in anhydrous 9

CH2Cl2 (50 mL) under nitrogen. While stirring at 0 °C, SnCl4 (3 mL, 25 mmol) was slowly added. The 10

resulting solution was stirred for 10 min at 0 °C. The previously synthesized acid chloride (3.75 g, 21 11

mmol) in anhydrous CH2Cl2 (30 mL) was then added. The reaction mixture was stirred for 2 h at 0 °C 12

then quenched via the addition of HCl (1 M, 35 mL). After 15 min stirring the mixture was extracted 13

with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine and then dried 14

(Na2SO4). After evaporation of the solvent under reduced pressure the crude material was purified using 15

flash chromatography (SiO2, EtOAc/hexane 3/7 to 4/6) to give compound 3 as an off white solid (5.1 g, 16

66%) and compound 4 as a white solid (1.2 g, 24%). Benzyl 4-(5-ethoxy-5-oxopentanoyl)-3,5-dimethyl-17

1H-pyrrole-2-carboxylate (3): 1H NMR (CDCl3, 500 MHz) δ 1.24 (t, J = 7.0 Hz, 3H), 2.02-2.04 (m, 18

2H), 2.40 (t, J = 7.0 Hz, 2H) 2.49 (s, 3H), 2.60 (s, 3H) 2.80 (t, J = 7.0 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H) 19

5.31 (s, 2H), 7.33-7.42 (m, 5H) 8.98 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ 13.2, 14.6, 15.6, 19.7, 20

33.9, 42.0, 60.6, 66.5, 117.9, 123.8, 128.6, 128.7, 129.0, 130.0, 136.3, 138.5, 161.5, 173.7, 197.4; 21

HRMS-ESI (m/z): [M+Na]+ calcd for C21H25N1Na1O5, 394.1625; found, 394.1605. 4-(5-Ethoxy-5-22

oxopentanoyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (4): 1H NMR (DMSO, 300 MHz) δ 1.17 (t, J 23

= 7.2 Hz, 3H), 1.75-1.85 (m, 2H), 2.33 (t, J = 7.5 Hz, 2H) 2.42 (s, 3H), 2.47 (s, 3H) 3.30 (t, J = 6.9 Hz, 24

2H), 4.06 (q, J = 7.2 Hz, 2H), 11.7 (br s, 1H); 13C NMR (DMSO, 125 MHz) δ 12.3, 14.1, 14.4, 19.2, 25

19

32.9, 40.7, 59.7, 122.2, 128.0, 137.9, 142.6, 162.4, 172.8, 196.2; HRMS-ESI (m/z): [M+Na]+ calcd for 1

C14H19N1Na1O5, 304.1155; found, 304.1143. 2

(E)-Benzyl 3-(p-tolyl)acrylate 5i: To a suspension of (E)-4-methylcinnamic acid (500 mg, 3.08 mmol) 3

in CH2Cl2 (10 mL) was added EDC (525 mg, 3.39 mmol), DMAP (414 mg, 3.39 mmol) followed by 4

benzyl alcohol (480 µL, 4.62 mmol). The resulting solution was stirred for 18 h, and then water was 5

added (50 mL). The mixture was extracted with CH2Cl2 (3 × 30 mL). Then the combined organic layers 6

were washed with brine and then dried (Na2SO4). After evaporation of the solvent under reduced pres-7

sure the crude was purified using flash chromatography (SiO2, EtOAc/hexanes 1/9) to give a white solid 8

(380 mg, 49%). Mp 86 °C; 1H NMR (CDCl3, 500 MHz) δ 2.37 (s, 3H), 5.25 (s, 2H), 6.45 (d, J = 15.7 9

Hz, 1H), 7.20 (d, J = 8 Hz, 2H), 7.33-7.43 (m, 7H), 7.71 (d, J = 15.7 Hz, 1H); 13C NMR (CDCl3, 125 10

MHz) δ 21.6, 66.4, 116.9, 128.2, 128.4 (2C), 128.7, 129.8, 131.7, 136.3, 140.9, 145.3, 167.1; HRMS-11

ESI (m/z): [M+Na]+ calcd for C17H16Na1O2, 275.1043; found, 275.1050. 12

Benzyl propiolate 5j: To a suspension of potassium carbonate (4.47 g, 32.3 mmol) in DMF (15 mL), 13

propiolic acid (2.00 mL, 32.3 mmol) in DMF (8 mL) was added and stirred at 0°C. After 10 minutes, 14

benzyl bromide (3.20 mL, 26.9 mmol) was added and reaction mixture was warmed to 25 °C. The re-15

sulting solution was stirred for 2 h, then water was added (45 mL). The mixture was extracted with 16

EtOAc/hexanes 1/1 (3 x 30 mL). The combined organic layers were washed with brine and then dried 17


flash chromatography (SiO2, EtOAc/hexanes 1/19) to give a colorless oil (4.31 g, quantitative). 1H NMR 19

(CD2Cl2, 500 MHz) δ 2.96 (s, 1H), 5.20 (s, 2H), 7.35-7.40 (m, 5H); 13C NMR (CD2Cl2, 125 MHz) δ 20

68.3, 74.8, 75.2, 128.9, 129.01, 129.04, 135.2, 152.8; HRMS-ESI (m/z): [M+Na]+ calcd for C10H8NaO2, 21

183.0417; found, 183.0417. 22

4-Methoxybenzyl pentanoate 5k: To a stirring solution of 4-methoxybenzyl alcohol (0.30 mL, 2.42 23

mmol) in DCM (8.0 mL) at 0 °C, triethylamine (0.49 mL, 4.83 mmol) and valeroyl chloride (0.29 mL, 24

2.42 mmol) was added. The reaction was stirred for 1 h and then a further aliquot of valeroyl chloride 25

20

(0.17 mL, 1.45 mmol) was added. The reaction mixture was quenched with water (15 mL), and then 1

extracted into CH2Cl2 (3 x 15 mL). The combined organic layers were washed with brine and then dried 2


flash chromatography (SiO2, EtOAc/hexanes 1/9) to give a colorless oil (336 mg, 63%). 1H NMR 4

(CD2Cl2, 500 MHz) δ 0.89 (t, J = 7.5 Hz, 3H) 1.33 (se, J = 7.5 Hz, 2H), 1.58 (qn, J = 7.5 Hz, 2H), 2.30 5

(t, J = 7.5 Hz, 2H), 3.78 (s, 3H), 5.01 (s, 2H), 6.87 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H); 13C 6

NMR (CD2Cl2, 125 MHz) δ 13.8, 22.6, 27.4, 34.4, 55.6, 66.1, 114.2, 128.9, 130.2, 160.0, 173.8; HRMS-7


Benzyl ethyl adipate 7c: to a solution of 6-ethoxy-6-oxohexanoic acid (1.1 g, 6.3 mmol) in anhydrous 9

DCM (5 mL) was added SOCl2 (570 µL, 7.9 mmol) and the reaction mixture was heated at 45 °C for 10

two hours. Then benzyl alcohol (720 µL, 6.9 mmol) was added at room temperature. The reaction mix-11

ture was heated at 40 °C for 3 hours then cooled to room temperature. An aqueous solution of NaOH 12

(10%, 20 mL) was added and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organ-13

ic layers were washed with brine (50 mL), and then dried (Na2SO4). After evaporation of the solvent 14

under reduced pressure the crude material was purified using flash chromatography (SiO2, 15

EtOAc/hexanes 1/9) to give a colorless oil (600 mg, 36%). 1H NMR (CDCl3, 300 MHz) δ 1.24 (t, J = 16

7.0 Hz, 3H), 1.65-1.70 (m, 4H), 2.31 (t, J = 7.0 Hz, 2H) 2.38 (t, J = 7.0 Hz, 2H), 4.12 (q, J = 7.0 Hz, 17

2H), 5.11 (s, 2H), 7.33-7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 24.5, 34.0, 60.4, 66.3, 128.3, 18

128.7, 136.1, 173.2, 173.4; HRMS-ESI (m/z): [M+Na]+ calcd for C15H20Na1O4, 287.1254; found, 19

287.1259. 20

2,2,2-Trichloro-1-phenylethyl (3-phenylpropyl)carbamate 7g: To a solution of 3-phenylpropan-1-21

amine (314 µL, 2.2 mmol) in anhydrous CH2Cl2 (12 mL) was added CDI (390 mg, 2.4 mmol) and the 22

reaction mixture was stirred at 40 °C for 2h30. It was cooled to room temperature, then water (30 mL) 23

was added and the mixture was extracted with Et2O (3 × 30 mL). The combined organic layers were 24

21

washed with brine (50 mL), dried (Na2SO4) and the solvent were removed under reduced pressure to 1

give N-(3-phenylpropyl)-1H-imidazole-1-carboxamide as a white solid (500 mg, quant.) 2

To a solution of 2,2,2-trichloro-1-phenylethanol (250 mg, 1.1 mmol)72 in anhydrous THF (2 mL) 3

was added NaH (60% in oil, 1.33 mmol) at 0°C. The reaction was run at this temperature for 30 min 4

then a solution of N-(3-phenylpropyl)-1H-imidazole-1-carboxamide (250 mg, 1.1 mmol) in anhydrous 5

THF (2mL) was added. The reaction mixture was stirred 3 h at room temperature then quenched by the 6

addition of water (10 mL) and extracted with Et2O (3 × 30 mL). The combined organic layers were 7

washed with brine (50 mL), and then dried (Na2SO4). After evaporation of the solvent under reduced 8

pressure the crude material was purified using flash chromatography (SiO2, CH2Cl2/hexanes 5/5) to give 9

a colorless oil (311 mg, 70%). 1H NMR (CDCl3, 300 MHz) δ 1.86 (quint., J = 7.4 Hz, 2H), 2.65 (t, J = 10

7.6 Hz, 2H), 3.17-3.31 (m, 2H), 4.99 (br s, 1H), 6.30 (s, 1H), 7.14-7.21 (m, 3H), 7.25-7.28 (m, 2H), 11

7.38-7.41 (m, 3H), 7.59-7.62 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 31.5, 33.1, 41.0, 83.3, 126.2, 12

128.0, 128.5, 128.6, 129.7, 129.8, 133.6, 141.3, 154.2. HRMS-ESI (m/z): [M+Na]+ calcd for 13

C18H18Cl3N1Na1O2, 408.0295; found, 408.0278. 14

(2-(Benzyloxy)propyl)benzene 7i: Following a literature procedure,73 1-phenylpropan-2-ol (500 mg, 15

3.67 mmol) was dissolved in MeNO2 (20 mL) then benzaldehyde (440 µL, 4.3 mmol), FeCl3 (35 mg, 5 16

mol%) and Et3SiH (590 mL, 3.67 mmol) were added under N2. The reaction mixture was stirred two 17

hours then quenched through the addition of phosphate buffer (pH = 7, 20 mL). The reaction mixture 18

was extracted with EtOAc (3 × 30 mL) and the combined organic layers were washed with brine (50 19

mL) then dried (Na2SO4). After evaporation of the solvents under reduced pressure the crude material 20

was purified using flash chromatography (SiO2, EtOAc/hexanes 0.3/99.7) to give a colorless oil (730 21

mg, 94%). 1H NMR (CDCl3, 300 MHz) δ 1.20 (d, J = 6.0 Hz, 3H), 2.70 (dd, J = 13.5, 6.3 Hz, 1 H), 2.97 22

(dd, J = 13.5, 6.3 Hz, 1 H), 3.74 (se. J = 6.3 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 23

1H), 7.19-7.38 (m, 10H); 13C NMR (CDCl3, 100 MHz) δ 19.7, 43.4, 70.7, 76.3, 126.2, 127.5, 127.7, 24

22

128.3, 128.4, 129.7, 139.0, 139.2; HRMS-ESI (m/z): [M+Na]+ calcd for C16H18Na1O1, 249.1250; found, 1

249.1253. 2

(3-(Methoxymethoxy)propyl)benzene 7o: To a solution of 1-phenylpropan-2-ol (500 mg, 3.67 mmol) 3

in anhydrous THF (15 mL) was added DIPEA (1.4 mL, 8.07 mmol) followed by MOMCl (300 µL, 4.01 4

mmol). The reaction mixture was stirred for 16 h then quenched with a saturated aqueous solution of 5

NH4Cl (15 mL) for 15 min. The reaction mixture was then extracted with EtOAc (3 × 30 mL) and the 6

combined organic layers were washed with brine (50 mL) and then dried (Na2SO4). After evaporation of 7

the solvent under reduced pressure the crude material was purified using flash chromatography (SiO2, 8

EtOAc/hexanes 0.5/99.5) to give a colorless oil (450 mg, 68%). 1H NMR (CDCl3, 300 MHz) δ 1.88-9

1.97 (m, 2H), 2.72 (t, J = 7.8 Hz, 2H), 3.38 (s, 3H), 3.56 (t, J = 6.5 Hz, 2H), 4.64 (s, 2H), 7.16-7.21 (m, 10

3H), 7.26-7.31 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 31.6, 32.6, 55.3, 67.3, 96.6, 126.0, 128.5, 128.6, 11

142.0; HRMS-ESI (m/z): [M+Na]+ calcd for C11H16Na1O2, 203.1043; found, 203.1043. 12

Benzyl 2-(4-((benzyloxy)methyl)phenyl)acetate 7r:73 To a solution of benzyl 2-(4-13

(hydroxymethyl)phenyl)acetate74 (500 mg, 3.67 mmol) in nitromethane (20 mL) under nitrogen was 14

added benzaldehyde (440 µL, 4.3 mmol), FeCl3 (35 mg, 5 mol%) and then triethylsilane (590µL, 3.67 15

mmol). The reaction mixture was stirred for 2 h under nitrogen then was quenched by the addition of a 16

phosphate buffer (50 mL, pH = 7). The crude mixture was extracted with EtOAc (3 × 20 mL) and the 17

combined organic layers were washed with brine and then dried (Na2SO4). After evaporation of the sol-18

vent under reduced pressure the crude material was purified using flash chromatography (SiO2, 19

EtOAc/hexanes 0.5/99.5) to give a colorless oil (730 mg, 94%). 1H NMR (CDCl3, 300 MHz) δ 3.68 (s, 20

2H), 4.56 (s, 4H), 5.14 (s, 2H), 7.27-7.38 (m, 14H); 13C NMR (CDCl3, 100 MHz) δ 41.2, 66.8, 71.9, 21

72.2, 127.8, 127.9, 128.1, 128.3, 128.4, 128.5, 128.7, 129.5, 133.4, 136.0, 137.4, 138.4, 171.5. HRMS-22


Benzyl 3-(3-(benzylamino)propoxy)benzoate 7s: To a solution of benzyl 3-hydroxybenzoate37 (500 24

mg, 2.2 mmol) in DMF (10 mL) at 0 °C under nitrogen was added NaH (60% in grease, 2.6 mmol). The 25

23

suspension was stirred for 30 min at room temperature then cooled to 0 °C. A solution of 3-((tert-1

butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate38 in DMF (10 mL) was then added and the 2

reaction mixture was stirred for a further 3 h at room temperature. The reaction was quenched through 3

the addition of water (100 mL) and the reaction mixture was extracted with EtOAc (3 × 30 mL). The 4

combined organic layers were washed with water (50 mL), brine (50 mL) and then dried (Na2SO4). Af-5

ter evaporation of the solvent under reduced pressure the crude material was purified using flash chro-6

matography (SiO2, EtOAc/hexanes 2/8 then 3/7) to give benzyl 3-(3-((tert-7

butoxycarbonyl)amino)propoxy)benzoate as a white solid (570 mg, 67%). Mp 80 °C; 1H NMR (CDCl3, 8

300 MHz) δ 1.44 (s, 9H), 1.99 (qn, J = 6.3 Hz, 2H), 3.33 (q, J = 6.3 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 9

4.74 (br s, 1H), 5.36 (s, 2H), 7.09 (ddd, J = 8.4, 2.7, 0.9 Hz, 1H), 7.31-7.46 (m, 5H), 7.58 (dd, J = 2.7, 10

1.6 Hz, 1H), 7.67 (dt, J = 7.8, 1.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 28.5, 29.7, 38.1, 66.1, 66.9, 11

115.1, 120.0, 122.4, 128.3, 128.4, 128.7, 129.6, 131.6, 136.2, 156.1, 158.9, 166.4; HRMS-ESI (m/z): 12

[M+Na]+ calcd for C22H27N1Na1O5, 408.1781; found, 408.1795. 13

Benzyl 3-(3-((tert-butoxycarbonyl)amino)propoxy)benzoate (520 mg, 1.34 mmol) was dis-14

solved in CH2Cl2 (5 mL) then TFA (1 mL) was added. The reaction mixture was stirred for 3 h at room 15

temperature then water (50 mL) was added. The crude mixture was then extracted with DCM (3 × 20 16

mL) then the combined organic layers were washed with NaHCO3 (50 mL), brine (50 mL) and then 17

dried (Na2SO4). The obtained oil (430 mg, 1.34 mmol) was dissolved in DCM (3 mL) and MgSO4 (160 18

mg, benzaldehyde (180 µL, 1.8 mmol) and triethylamine (250 µL, 1.8 mmol) were added under nitro-19

gen. The reaction was stirred overnight then filtered through a pad of Celite using CH2Cl2. The filtrate 20

was concentrated under reduce pressure then the resulting oil was dissolved in MeOH (5 mL). NaBH4 21

(68 mg, 1.8 mmol) was added in portions at 0 °C then the reaction mixture was stirred at room tempera-22

ture for 1 h. The reaction was quenched through the addition of water (20 mL) and the reaction mixture 23

was then extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine (50 24

mL) and then dried (Na2SO4). After evaporation of the solvent under reduced pressure the crude mate-25

24

rial was purified using flash chromatography (Al2O3 neutral Brockman type III, CH2Cl2 100% then 1

CH2Cl2/MeOH 99/1) to give 7s colorless oil (300 mg, 53%). 1H NMR (CDCl3, 300 MHz) δ 1.46 (br s, 2

1H), 2.00 (qn, J = 6.5 Hz, 2H), 2.83 (t, J = 7.0 Hz, 2H), 3.81 (s, 2H), 4.09 (t, J = 6.5 Hz, 2H), 5.36 (s, 3

2H), 7.08 (dd, J = 8.0, 2.5 Hz, 1H), 7.22-7.26 (m, 1H), 7.29-7.40 (m, 8H), 7.44-7.45 (m, 1H), 7.59 (br s, 4

1H), 7.66 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 29.9, 46.3, 54.2, 66.7, 66.9, 115.1, 120.0, 5

122.2, 127.1, 128.2, 128.3, 128.4, 128.5, 128.7, 129.5, 131.6, 136.2, 140.5, 159.1, 166.5. HRMS-ESI 6

(m/z): [M+H]+ calcd for C24H26N1O3, 376.1907; found, 376.1915. 7

N-Benzylcarbamate-O-Benzyl-L-serine methyl ester 7t: (S)-Methyl 2-(((benzyloxy)carbonyl)amino)-8

3-hydroxypropanoate75 (200 mg, 0.79 mmol) was dissolved in CH2Cl2 (3 mL) then BnBr (100 µL, 0.87 9

mmol) and silver oxide (274 mg, 1.18 mmol) were added. The suspension was stirred in the dark for 20 10

h then filtered. After evaporation of the solvent under reduced pressure the crude material was purified 11

using flash chromatography (SiO2, EtOAc/hexanes 3/7) to give a colorless oil (150 mg, 55%). 1H NMR 12

(CDCl3, 500 MHz) δ 3.70 (dd, J = 9.6, 3.3 Hz, 1H), 3.75 (s, 3H), 3.89 (dd, J = 9.6, 3.3 Hz, 1H), 4.45-13

4.56 (m , 3H), 5.12 (s, 2H), 5.63 (d, J = 8.7 Hz, 1H), 7.24-7.37 (m, 10H); 13C NMR (CDCl3, 125 MHz) 14

δ 52.7, 54.5, 67.2, 69.9, 73.4, 127.7, 128.0, 128.2, 128.3, 128.6, 128.7, 136.4, 137.6, 156.1, 170.9; 15

HRMS-ESI (m/z): [M+Na]+ calcd for C19H21N1Na1O5, 366.1312; found, 366.1299. 16

N-Benzyl-O-Benzyl-L-serine benzyl ester 7u: Following the previous procedure and starting from (S)-17

benzyl 2-(benzylamino)-3-hydroxypropanoate,76 7u was obtained as a colorless oil (110 mg, 20%). 1H 18

NMR (CDCl3, 300 MHz) δ 2.46 (br s, 1H), 3.60-3.67 (m, 3H), 3.73-3.79 (m, 2H), 3.90 (d, J = 13.5 Hz, 19

2H), 5.25 (aq, J = 11.8 Hz, 2H), 7.23-7.33 (m, 10H), 7.39-7.43 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 20

55.0, 59.5, 62.0, 66.6, 127.6, 128.6, 128.7, 128.8, 129.1, 135.8, 138.8, 171.3 (6 carbon signals non ac-21

counted for); HRMS-ESI (m/z): [M+Na]+ calcd for C24H25N1Na1O3, 398.1727; found, 398.1720. 22

Compounds from Table 3: 23

25

General procedure for deprotection of benzyl esters/carbamates (GPD): The benzyl protected mate-1

rial (5) (0.826 mmol, 1 equiv) was dissolved in anhydrous CH2Cl2 (1.8 mL) under nitrogen. While stir-2

ring, SnCl4 (0.413 mmol, 0.5 equiv) was added. The reaction vessel was then sealed and heated to 40°C 3

overnight (for convenience, although analysis using TLC indicated that many reactions progressed at 4

room temperature and/or were complete in just a few hours). The reaction was quenched with HCl (1 M, 5

1 mL) then extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine 6

then dried (Na2SO4) and the product was purified via recrystallization or column chromatography. 7

Benzoic acid 6a from benzyl benzoate 5a: Following GPD, 6a was synthesized from 5a (white crys-8

talline solid, 80%). 1H NMR (CDCl3, 300 MHz) δ 7.46-7.51 (m, 2H), 7.60-7.66 (m, 1H), 8.15 (d, J = 9 9

Hz, 2H). NMR data matches that previously reported for this compound.77 10

Benzoic acid 6a from 4-methoxybenzyl benzoate 5m: Following GPD, 6a was synthesized from 5m 11

(white crystalline solid, 86%). 1H NMR (DMSO, 300 MHz) δ 7.50 (t, J = 7.7 Hz, 2H), 7.62 (t, J = 7.5 12

Hz, 1H), 7.94 (d, J = 7.0 Hz, 2H), 12.96 (s, 1H). NMR data matches that previously reported for this 13

compound.77 14

4-Nitrobenzoic acid 6b: Following GPD, 6b was synthesized from 5b (white yellow/white crystalline 15

solid, quantitative). 1H NMR (DMSO, 300 MHz) δ 8.17 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 8.8 Hz, 2H), 16

13.64 (br s, 1H). NMR data matches that previously reported for this compound.77 17

4-Methoxybenzoic acid 6c: Following GPD, 6c was synthesized from 5c (off-white solid, 92%). 1H 18

NMR (DMSO, 500 MHz) δ 3.82 (s, 3H), 7.01 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 12.65 (br s, 19

1H). NMR data matches that previously reported for this compound.77 20

Pentanoic acid 6d from benzyl pentanoate 5d: Following GPD, 6d was synthesized from 5d (color-21

less oil, 82%). 1H NMR (CDCl3, 300 MHz) δ 0.93 (t, J = 7.5 Hz, 3H), 1.39 (qn, J = 7.5 Hz, 2H), 1.63 22

(qn, J = 7.5 Hz, 2H), 2.36 (t, J = 7.5 Hz, 2H). NMR data matches that previously reported for this com-23

pound.78 24

26

Pentanoic acid 6d from 4-methoxybenzyl pentanoate 5k: Following GPD, 6d was synthesized from 1

5k (colorless oil, 85%). 1H NMR (CDCl3, 500 MHz) δ 0.92 (t, J = 7.5 Hz, 3H), 1.37 (qn, J = 7.5 Hz, 2

2H), 1.63 (qn, J = 7.5 Hz, 2H), 2.36 (t, J = 7.5 Hz, 2H). NMR data matches that previously reported for 3

this compound.78 4

Tetradecanoic acid 6e: Following GPD, 6e was synthesized from 5e (white crystalline solid, 80%). 1H 5

NMR (CDCl3, 300 MHz) δ 0.88 (t, J = 6.9 Hz, 3H), 1.26-1.33 (m, 20H), 1.58-1.68 (m, 2H), 2.35 (t, J = 6

7.2 Hz, 2H). NMR data matches that previously reported for this compound.79 7

Pivalic acid 6f from benzyl pivalate 5f: Following GPD, 6f was synthesized from 5f (white/colorless 8

crystalline solid, quantitative). 1H NMR (CDCl3, 300 MHz) δ 1.22 (s, 9H). NMR data matches that pre-9

viously reported for this compound.80 10

Pivalic acid 6f from 4-methoxybenzyl pivalate 5l: Following GPD, 6f was synthesized from 5l, 11

white/colorless crystalline solid (80%). 1H NMR (CDCl3, 300 MHz) δ 1.24 (s, 9H). NMR data matches 12

that previously reported for this compound.80 13

2-(4-Methoxyphenyl)acetic acid 6g: Following GPD, 6g was synthesized from 5g (off-white flaky 14

solid, 96%). 1H NMR (CDCl3, 500 MHz) δ 3.59 (s, 2H), 3.80 (s, 3H), 6.87 (d, J = 8.5 Hz, 2H), 7.20 (d, 15

J = 9 Hz, 2H). NMR data matches that previously reported for this compound.81 16

Pent-4-enoic acid 6h: Following GPD, 6h was synthesized from 5h (colorless solid, quantitative). 1H 17

NMR (CDCl3, 500 MHz) δ 2.37-2.41 (m, 2H), 2.45-2.48 (m, 2H), 5.02-5.10 (m, 2H), 5.80-5.88 (m, 18

2H). NMR data matches that previously reported for this compound.82 19

(E)-3-(p-Tolyl)acrylic acid 6i: Following GPD, 6i was synthesized from 5i (white solid, 90%). 1H 20

NMR (CDCl3, 300 MHz) δ 2.39 (s, 3H), 6.41 (d, J = 15.9 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 21

8.1 Hz, 2H), 7.76 (d, J = 15.9 Hz, 1H). NMR data matches that previously reported for this compound.83 22

Propiolic acid 6j: Since propiolic acid is highly water soluble, rendering product isolation challenging 23

and thus the yield inaccurate, this reaction was performed and monitored in an NMR tube. Benzyl pro-24

piolate 5k (0.132 g, 0.826 mmol) was dissolved in deuterated dichloromethane (1.0 mL) in an NMR 25

27

tube. At 25°C the reaction was initiated via the addition of SnCl4 (47 µL, 0.413 mmol). Reaction pro-1

gress was monitored via collection of 1H NMR and 119Sn NMR spectra immediately after initiation and 2

then after 1, 3, 5 and 21 h. A 13C NMR spectrum was collected after 21 h. 100% conversion based on 3

NMR data. The data for this crude sample was compared to commercially obtained propiolic acid. 1H 4

NMR (CD2Cl2, 500 MHz) δ 3.17 (s, 1H), 3.82 (br s, polymer), 7.14 (br s, polymer), 10.82 (br s, 1H); 5

13C NMR (CD2Cl2, 125 MHz) δ 73.9, 78.4, 126.3 (polymer), 128.7 (polymer), 129.1 (polymer), 129.2 6

(polymer), 157.3. 7


Benzoic acid 6a from tert-butyl benzoate 7a: Following GPD, 6a was synthesized from 7a (white 9

crystalline solid, 76%). 1H NMR (CDCl3, 300 MHz) δ 7.46-7.52 (m, 2H), 7.60-7.66 (m, 1H), 8.12-8.15 10

(m, 2H). NMR data matches that previously reported for this compound.77 11

Ethyl benzoate 7b: Was subjected to GPD conditions and isolated after extraction as a white solid (340 12

mg, 96%). 1H NMR (CDCl3, 300 MHz) δ 1.39 (t, J = 7.2 Hz, 3H), 4.38 (q, J = 7.2 Hz, 2H), 7.39-7.45 13

(m, 2H), 7.51-7.56 (m, 1H), 8.03-8.06 (m, 2H). NMR data matches that previously reported for this 14

compound.59 15

6-Ethoxy-6-oxohexanoic acid 8c: Following GPD, 8c was synthesized from 7c (white solid 79%). 1H 16

NMR (CDCl3, 300 MHz) δ 1.25 (t, J = 7.2 Hz, 3H), 1.66-1.71 (m, 4H), 2.30-2.41 (m, 4H), 4.13 (q, J = 17

7.2 Hz, 2H). NMR data matches that previously reported for this compound.84 18

N-Benzyl-N-methyl-2-phenylethanamine 7d: Was subjected to GPD conditions and isolated after ex-19

traction (yellow film, 99%). 1H NMR (CDCl3, 300 MHz) δ 2.26 (s, 3H), 2.64-2.65 (m, 2H), 2.80-2.83 20

(m, 2H), 3.55 (s, 2H), 7.13-7.16 (m, 3H), 7.20-7.27 (m, 7H). NMR data matches that previously report-21

ed for this compound.60 22

N-Benzyl-3-methylbutanamide 7e: Was subjected to GPD conditions and isolated after extraction 23

(colorless oil, quant). 1H NMR (CDCl3, 300 MHz) δ 0.96 (d, J = 6.6 Hz, 6H), 2.10-2.23 (m, 3H), 4.45 d, 24

28

J = 5.7 Hz, 2H), 5.73 (br s, 1H), 7.26-7.37 (m, 5H). NMR data matches that previously reported for this 1

compound.61 2

3-Phenylpropylamine 8f: Following GPD but using 1.5 equiv of SnCl4, 8f was synthesized from 7f 3

(colorless oil, 79%). 1H NMR (CDCl3, 500 MHz) δ 1.25 (br s, 2H), 1.75-1.81(m, 2H), 2.66 (t, J = 7.5 4

Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 7.17-7.20 (m, 3H), 7.26-7.29 (m, 2H). NMR data matches that previ-5

ously reported for this compound.85 6

2,2,2-Trichloro-1-phenylethyl (3-phenylpropyl)carbamate 7g: Was subjected to GPD conditions and 7

isolated after extraction (colorless oil, quant). 1H NMR (CDCl3, 300 MHz) δ 1.86 (qn, J = 7.4 Hz, 2H), 8

2.65 (t, J = 7.6 Hz, 2H), 3.24 (qn, J = 6.4 Hz ,2H), 5.03 (br s, 1H), 6.31 (s, 1H), 7.15-7.21 (m, 3H), 7.28-9

7.31 (m, 2H), 7.38-7.42 (m, 3H), 7.60-7.62 (m, 2H). NMR data matches that of the starting material. 10

Compounds from Table 5 11

(3-(Benzyloxy)propyl)benzene 7h: Was subjected to GPD conditions and isolated after extraction (col-12

orless oil, quant). 1H NMR (CDCl3, 300 MHz) δ 1.81-1.91 (m, 2H), 2.64 (t, J = 6.3 Hz, 2H), 3.41 (t, J = 13

6.3 Hz, 2H), 4.43 (s, 2H), 7.08-7.11 (m, 3H), 7.16-7.27 (m, 7H). NMR data matches that previously 14

reported for this compound.63 15

(2-(Benzyloxy)propyl)benzene 7i: Was subjected to GPD conditions and isolated after purification us-16

ing column chromatography (SiO2, EtOAc/hexanes 1/9) (colorless oil, quant). 1H NMR (CDCl3, 300 17

MHz) δ 1.19 (d, J = 6.0 Hz, 3H), 2.70 (dd, J = 13.5, 6.3 Hz, 1 H), 2.97 (dd, J = 13.5, 6.3 Hz, 1 H), 3.73 18

(q, J = 6.3 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 7.18-7.31 (m, 10H). NMR data 19

matches that of the starting material. 20

Ethyl 4-(benzyloxy)benzoate 7j: Was subjected to GPD conditions and isolated after purification using 21

column chromatography (SiO2, EtOAc/hexanes 1/9) (white solid, 95%). 1H NMR (CDCl3, 300 MHz) δ 22

1.38 (t, J = 7.2 Hz, 3H), 4.35 (q, J = 7.2 Hz, 2H), 5.12 (s, 2H), 6.99 (d, J = 9.0 Hz, 2H), 7.34-7.45 (m, 23

5H), 8.00 (d, J = 9.0 Hz, 2H). NMR data matches that previously reported for this compound.64 24

29

1-(Benzyloxy)-4-methylbenzene 7k: Was subjected to GPD conditions and followed by TLC. TLC 1

showed complete conversion of 7k to p-cresol. 2

1-(Benzyloxy)-4-methoxybenzene 7l: Was subjected to GPD conditions and followed by TLC. TLC 3

showed complete conversion of 7l to 4-methoxyphenol along with byproducts. 4

3-Phenylpropyl 4-methylbenzenesulfonate 7m: Was subjected to GPD conditions and isolated after 5

extraction (colorless oil, quant). 1H NMR (CDCl3, 300 MHz) δ 1.91-2.01 (m, 2H), 2.46 (s, 3H), 2.65 (t, 6

J = 7.5 Hz, 2H), 4.04 (t, J = 6.3 Hz, 2H), 7.05-7.08 (m, 2H), 7.17-7.27 (m, 3H), 7.34 (d, J = 7.8 Hz, 2H), 7

7.79 (d, J = 8.4 Hz, 2H). NMR data matches that previously reported for this compound.67 8

3-Phenylpropan-1-ol 8n: Following GPD, 8n was synthesized from 7n and isolated after purification 9

using column chromatography (SiO2, EtOAc/hexanes 6/4) (colorless oil, 84%). 1H NMR (CDCl3, 300 10

MHz) δ 1.33 (br s, 1H), 1.90-2.00 (m, 2H), 2.76 (t, J = 7.6 Hz, 2H), 3.73 (t, J = 6.4, 2H), 7.23-7.26 (m, 11

3H), 7.30-7.36 (m, 2H). NMR data matches that previously reported for this compound.86 12

Triisopropyl(3-phenylpropoxy)silane 7p: Was subjected to GPD conditions and isolated after purifica-13

tion using column chromatography (SiO2, EtOAc/hexanes 0.3/99.7) (colorless oil, 85%). 1H NMR 14

(CDCl3, 300 MHz) δ 1.05-1.09 (m, 21H), 1.81-1.91 (m, 2H), 2.71 (t, J = 7.6 Hz, 2H), 3.72 (t, J = 6.3 15

Hz, 2H), 7.17-7.31 (m, 5H). NMR data matches that previously reported for this compound.70 16

Tert-butyldimethyl(3-phenylpropoxy)silane 7q: Was subjected to GPD conditions and isolated after 17

purification using column chromatography (SiO2, EtOAc/hexanes 1/9) (colorless oil, 36%). 1H NMR 18

(CDCl3, 300 MHz) δ 0.05 (s, 6H), 0.91 (s, 9H), 1.79-1.89 (m, 2H), 2.65-2.70 (m, 2H), 3.64 (t, J = 6.3 19

Hz, 2H), 7.17-7.20 (m, 2H), 7.25-7.28 (m, 3H). NMR data matches that previously reported for this 20

compound.70 21

22


30

O-Benzyl-L-serine methyl ester hydrochloride 8t: Following GPD conditions from 7t but using 1.0 1

equiv of SnCl4. The reaction was quenched with HCl (1M), and the pH then adjusted to pH 7 using 2

NaHCO3. The aqueous layer was extracted with CH2Cl2 (3 ×10 mL). The combined organic layers were 3

washed with brine then dried (Na2SO4). After evaporation of the solvent, the crude product was dis-4

solved in Et2O (3 mL) and a solution of HCl (2 M) in Et2O (300 µL) was added. The white solid ob-5

tained was collected using filtration (white solid, 55%). 1H NMR (CDCl3, 300 MHz) δ 3.76 (s, 3H), 6

3.94-4.00 (m, 1H), 4.08-4.11 (m, 1H), 4.36 (br s, 1H) 4.49 (d, J = 12.0 Hz, 1H), 4.68 (d, J = 12.0 Hz, 7

1H), 7.23-7.31 (m, 5H), 8.86 (br s, 3H). NMR data matches that previously reported for this 8

compound.87 9

N-Benzyl-O-Benzyl-L-serine 8u: Following GPD conditions, from 7u but using 1.0 equiv of SnCl4. 10

The reaction was quenched with a saturated aqueous solution of NaHCO3 and purified using flash 11

chromatography (SiO2, CH2Cl2/MeOH 9/1) (colorless oil, 30%). 1H NMR (CDCl3, 300 MHz) δ 3.65 (t, 12

J = 3.9 Hz, 1H), 3.88-3.99 (m, 4H), 4.04 (d, J = 7.8 Hz, 2H), 7.18-7.26 (m, 10H); 13C NMR (CDCl3, 125 13

MHz) δ 55.3 (2C), 59.0, 63.6, 128.6 (2C), 129.1 (2C), 129.6 (2C), 135.5 (2C), 172.4; HRMS-ESI (m/z): 14

[M+Na]+ calcd for C17H19N1Na1O3, 308.1257; found, 308.1259. 15

Benzyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside 7v: Was subjected to GPD conditions and isolated 16

after purification using column chromatography (SiO2, EtOAc/hexanes 1/9) (white solid, 57%). 1H 17

NMR (CDCl3, 300 MHz) δ selected data on α-7v 4.04 (t, J = 9.3 Hz, 1H). NMR data matches that pre-18

viously reported for this compound.88 19

ASSOCIATED CONTENT 20

Supporting Information. NMR spectra for new compounds and mass spectral data. This material is 21

available free-of-charge via the Internet at http://pubs.acs.org. 22

ACKNOWLEDGMENT 23

31

A.E.G.B. was supported by Cancer Care Nova Scotia (CCNS), by way of a Norah Stephen Oncology 1

Scholars Award through the Beatrice Hunter Cancer Research Institute (BHCRI). E.M. was BHCRI-2

supported with funds provided by CCNS as part of The Terry Fox Foundation Strategic Health Research 3

Training Program in Cancer Research at CIHR. 4

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